Haeberle et al. Trials (2020) 21:242 https://doi.org/10.1186/s13063-020-4163-0 STUDY PROTOCOL Open Access Therapeutic iloprost for the treatment of acute respiratory distress syndrome (ARDS) (the ThIlo trial): a prospective, randomized, multicenter phase II study Helene Haeberle1*, Stefanie Prohaska1, Peter Martus2, Andreas Straub1, Alexander Zarbock3, Gernot Marx4, Manola Zago5, Martin Giera6, Michael Koeppen1 and Peter Rosenberger1* Abstract Background: Acute respiratory distress syndrome (ARDS) is caused by rapid-onset (within hours) acute inflammatory processes in lung tissue, and it is a life-threatening condition with high mortality. The treatment of ARDS to date is focused on the prevention of further iatrogenic damage of the lung rather than the treatment of the initial inflammatory process. Several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ARDS, iloprost treatment resulted in improved oxygenation. Therefore, we plan to conduct a large multicenter trial to evaluate the effect of iloprost on ARDS. Methods: The Therapeutic Iloprost during ARDS trial (ThIlo trial) is a multicenter, randomized, single blinded, clinical phase II trial assessing the efficacy of inhaled iloprost for the prevention of the development and progression of ARDS in critically ill patients. One hundred fifty critically ill patients suffering from acute ARDS will be treated either by nebulized iloprost or NaCl 0.9% for 5 days. Blood samples will be drawn at defined time points to elucidate the serum levels of iloprost and inflammatory markers during treatment. Mechanical ventilation will be standardized. In follow-up visits at days 28 and 90 as well as 6 months after enrollment, functional status according to the Barthel Index and a health care-related questionnaire, and frailty (Vulnerable Elders Survey) will be evaluated. The primary endpoint is the improvement of oxygenation, defined as the ratio of PaO2/FiO2. Secondary endpoints include 90- day all-cause mortality, Sequential Organ Failure Assessment scores during the study period up to day 90, the duration of mechanical ventilation, the length of intensive care unit (ICU) stay, ventilator-associated pneumonia, delirium, ICU-acquired weakness, and discharge localization. The study will be conducted in three university ARDS centers in Germany. Discussion: The results of the ThIlo trial will highlight the anti-inflammatory effect of iloprost on early inflammatory processes during ARDS, resulting in the improvement of outcome parameters in patients with ARDS. Trial registration: EUDRA-CT: 2016-003168-37. Registered on 12 April 2017. ClinicalTrials.gov: NCT03111212. Registered on 4 June 2017. Keywords: ARDS, Iloprost, Inflammation, Intensive care, Ventilation * Correspondence: [email protected]; [email protected] 1Department of Anesthesiology and Intensive Care Medicine, University Hospital, Universitätsklinikum Tübingen, Universitätsklinikum Tübingen, Hoppe-Seyler-Straße 3, 72076 Tübingen, Germany Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Haeberle et al. Trials (2020) 21:242 Page 2 of 11 Background potential anti-inflammatory strategy for the treatment of Acute respiratory distress syndrome (ARDS) is defined the existing intra-alveolar inflammation or to intervene as pulmonary compromise with bilateral pulmonary in- in the development of intra-alveolar inflammation. For filtrates associated with moderate to severe hypoxemia this, patients were treated with aspirin, simvastatin, and [1]. The public health impact of ARDS is considerable, surfactant, but the tested treatments failed and did not and it is estimated that approximately 75,000 cases of have any significant effect [10–12]. ARDS occur annually in Germany. The estimated mor- tality ranges from 26 to 51% and depends on the severity Iloprost of the associated hypoxemia [2]. Patients surviving Considerable evidence in preclinical models shows that ARDS treatment also show reduced functional capacity the use of iloprost for the treatment of ARDS and pul- in their everyday life following hospitalization [3, 4]. monary inflammation might be of significant benefit. In Therefore, there is a pressing need to develop further small animal models, investigators showed that iloprost ARDS treatment strategies with a view to ultimately im- improves endothelial barrier function and reduces the proving patient outcomes. detrimental signs of pulmonary edema [13]. It also re- The bilateral pulmonary infiltrates that can be iden- duces the pulmonary sequestration of leukocytes and tified on chest radiography reflect the diffuse inflam- platelets, which is a central disease mechanism under- matory changes within the lung that are caused by lying the development of ARDS [14]. This evidence acute inflammation within the pulmonary tissue and could be transferred into different models of lung injury, the alveolar space. The initial inflammatory process is showing positive evidence for the reduction of pulmon- induced by the activation of the innate immune re- ary inflammation in a pressure-induced model of lung sponse by the binding of microbial products (patho- injury [15]. The anti-inflammatory effect was attributed gen-associated molecular patterns [PAMPs]) or cell to the cyclooxygenase-2 (COX-2) system and the in- injury-associated endogenous molecules (danger-asso- volvement of lipoxin A4 [16]. Ras-related protein 1 ciated molecular patterns [DAMPs]) to pattern recog- (RAP-1) might also be involved in the protective role of nition receptors (PRRs). Therefore, the common iloprost [17]. This positive anti-inflammatory effect of causes of ARDS are trauma, sepsis, pneumonia, blood iloprost on the pulmonary tissue was also demonstrated transfusion, or aspiration into the lungs. After the ini- in several models of ischemia-reperfusion (IR) injury. tial activation of the innate immune response, innate Furthermore, IR injury can also result in ARDS and pul- immune effector mechanisms, such as the formation monary failure. Iloprost was able to reduce this pulmon- of neutrophil extracellular traps (NETs), are activated, ary compromise in several preclinical studies [18–21]. which further aggravate the alveolar injury [5]. The The anti-inflammatory effect of iloprost was also shown resulting increased permeability of the microvascular in large animal models of lung injury using porcine barrier results in the extravascular accumulation of models of ARDS [22–24]. Here, again, iloprost showed protein-rich fluid that accumulates within the alveolar an anti-inflammatory effect. In addition, the shunt frac- space. The increased permeability is also linked to the tion could be reduced, which resulted in improved oxy- transfer of leukocytes (mostly neutrophil granulocytes) genation and improved pulmonary dynamics, which is and erythrocytes into the alveolar space in ARDS, as essential for the reinstitution of spontaneous ventilation well as to the presence of proinflammatory-regulated during and following ARDS [22, 23, 25–27]. This shows cytokines that increase the inflammatory burden that the preclinical data identified a beneficial effect of within the lung [5]. As a result, dysregulated inflam- iloprost on ARDS. So far, only one study on inhaled ilo- mation, the accumulation of leukocytes and platelets, prost in adult patients with ARDS has been conducted, and altered permeability of alveolar barriers remain although an application of inhaled iloprost is noted in the central pathophysiologic problems in ARDS [5, 6]. the guidelines of the Association of the Scientific Med- The treatment of ARDS to date is focused on the pre- ical Societies (AWMF) for the treatment of ARDS [28]. vention of further iatrogenic damage of the lung through The AWMF guidelines indicate that the use of ARDS lung-protective mechanical ventilation, neuromuscular can be considered, especially in patients with severe blockade, and conservative fluid management [7]. Recent ARDS who are mechanically ventilated and not self- clinical trials have focused on the role of ventilation consenting [7]. strategies in the prevention or treatment of ARDS using noninvasive ventilation devices or prone positioning [8, Methods/design 9]. Although these strategies have shown a positive effect Study design on patient oxygenation and symptoms, they do not ThIlo is a multicenter, randomized, single blinded clinical interfere with the underlying pathophysiological changes phase II trial assessing the efficacy of inhaled iloprost in of ARDS. Several interventions have tried to use a the development and progression of ARDS in critically ill Haeberle et al. Trials (2020) 21:242 Page 3 of 11 patients. Based on the risk of pulmonary hemorrhage, Exclusion criteria which is very rare—especially in patients with ARDS—the The exclusion criteria are defined